De Cunto, Giovanna

Lungarella, Giuseppe

Rahman, Irfan

Sundar, Isaac K.

American Journal of Respiratory Cell and Molecular Biology

Irfan Rahman

Giovanna De Cunto

Isaac K. Sundar

Giuseppe Lungarella

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Vulnerability and Genetic Susceptibility to Cigarette Smoke–Induced Emphysema in Mice

Archivio della Ricerca - Università degli Studi di Siena

EDITORIALSVulnerability and Genetic Susceptibility to Cigarette Smoke–InducedEmphysema in MiceCigarette smoke (CS) has been identiﬁed as the most importantrisk factor for the development of chronic obstructive pulmonarydisease (COPD). Studies of cigarette/tobacco smoke–inducedCOPD have primarily utilized small laboratory animals,particularly inbred laboratory mice, as the model of choice. Theﬁrst comprehensive review of animal models of emphysemarelating to the pathogenesis of COPD was published in 2002 (1),and a more recent review provided updates on this topic (2).The use of this species has several advantages, including arelatively low cost, a rapid reproductive cycle, large litter sizes, and theavailability of antibodies and molecular probes developed speciﬁcallyfor mouse research. In addition, many inbred strains and theirmutants (transgenic and knockout) are available and a high overallgenetic homology exists between the mouse and human genomes.Finally, mouse genes can be manipulated to create global as well asconditional mutants (using CRISPR/Cas and tissue-speciﬁc Cretransgenes). However, the mouse has limitations as an animal modelof COPD in that it does not fully recapitulate the human disease. Oneshould keep this limitation in mind when planning experiments andinterpreting results obtained in this species (3).Importantly, mice are obligatory nose breathers, so they exhibita different pattern of particle ﬁltration in the nares and upperrespiratory tract compared with humans. However, this does notinvalidate the methods commonly used to expose mice tocigarette/tobacco smoke, i.e., by nose only and by whole body,because both approaches model second-hand smoke exposure.Moreover, mouse submucosal glands are restricted to thetrachea, and mice lack a signiﬁcant population of goblet cells in theirbronchi and bronchioles. The appearance of clusters of goblet cells intheir bronchi/bronchioles after cigarette/tobacco smoke exposure islikely due to metaplasia and not hyperplasia. Additionally, mice do nothave respiratory bronchioles and therefore lack the anatomical basis forthe development of centrilobular emphysema, a lesion of respiratorybronchioles. Instead, they develop patchy emphysema.Mice can be exposed to CS delivered by a smoking machine vianose-only (4) or whole-body (5) exposure. The types of cigarettes,chemical emissions, and particulates used, the number of cigarettessmoked per day, and the duration of exposure (in months) havenot been standardized, so these aspects differ among laboratories.Generally, either reference (R series) cigarettes from the KentuckyTobacco Research and Development Center at the University ofKentucky (Lexington, KY) or the commercially available MarlboroRed cigarettes are used. The latter have the advantage of beingwidely available and commonly used by smokers. CS studies haveprovided a fundamental understanding of the complex pathogeniccellular and molecular processes, including genetic/epigeneticmechanisms, that are involved in the development of COPD andthe testing of potential therapeutics.Not all strains of mice develop emphysema after chronic CSexposure. In susceptible strains, the severity of emphysema is limitedand does not reach the extent seen in human smokers or in othermurine models of emphysema. The different susceptibilities toemphysema observed in three strains of mice have been linked tostrain-dependent differences in antioxidant defenses in response to CS(6). ICR mice were shown to have increased lung antioxidant defenses(possibly Nrf2, glutathione, glutaredoxin-1, and peroxiredoxin-6)when acutely exposed to CS, whereas C57BL/6J and DBA2 mice didnot (6). Of interest, C57BL/6J and DBA2 mice developed signiﬁcantemphysema when exposed to CS for 6–7 months, whereas ICRmice did not (6). Chronic CS exposure causes other cellularalterations; for example, impaired ciliated epithelial cell function wasobserved in C57BL/6J mice exposed to whole-body CS for up to 1 year(7). Another study of several mouse strains (i.e., NZWLac/J, A/J, SJ/L,and AKR/J) conﬁrmed the strain dependency response to CS andidentiﬁed other emphysema-resistant or susceptible strains(8). However, the genetic basis for that variability has not been studied.Recently, a recombinant inbred strain of mice, referred to as theCollaborative Cross (CC), was derived from random mixing of eightdifferent founder strains (9). This CC strain has a high phenotypicdiversity that closely mimics human disparity/diversity, thusenhancing investigators’ ability to map the causative loci underlyingcomplex disease-related traits (9). Future studies using the CC strainwill provide a better understanding of tobacco/CS-inducedCOPD/emphysema models at the level of systems genetics.In this issue of the Journal, Radder and colleagues (pp. 367–375) show that susceptibility to CS-induced emphysema asmeasured by alveolar chord length is a variable and continuoustrait in 34 inbred strains of mice (10). They demonstrate variousdegrees of susceptibility, ranging from no response (resistantCBA/J) to extremely susceptible (A/J). The C57BL/6J mice were thesecond most susceptible to CS. By testing the association of thisquantitative trait across the genome and then integrating mouseand human genome-wide scans, Radder and colleagues identiﬁedAbi3bp as a novel candidate gene contributing to emphysemasusceptibility. This gene encodes for ABI family member 3 bindingprotein (also known as TARSH or eratin), a putative tumorsuppressor that is predominantly expressed in the lung.Intriguingly, this protein controls the growth and differentiation ofstem and tumor cells while it also promotes senescence in somecells via a p21-dependent pathway (11). Cellular senescence is oneof several molecular mechanisms that have been shown to mediateCOPD pathogenesis (12). The potential role of the Abi3bp gene inpulmonary emphysema requires more investigation in humans andlaboratory animals (i.e., knockout mice for Abi3bp) to establish themechanistic contribution of this gene to emphysema susceptibility.In addition to the study limitations identiﬁed by the authors,only female mice were used, and sex-speciﬁc differences may beimportant (13). Also, the authors were unable to detect anyregions that strictly met multiple testing correction thresholds.Importantly, alveolar chord length is not a correlate/measure foremphysema, and emphysema is only one pathological entity ofCOPD. The moderate functional and anatomical responses to270 American Journal of Respiratory Cell and Molecular Biology Volume 57 Number 3 | September 2017chronic CS exposure in animals are certainly another importantlimiting factor. There is a lack of information about various lungmechanical properties (e.g., compliance, resistance, and pressure-volume), although the authors used the ﬂexiVent system (SCIREQ,Montreal, Quebec, Canada) for forced oscillatory mechanicsmeasurements and provided the tissue elastance H data.Nevertheless, the ﬁndings in this study point to a novel intrinsicfactor that may be an important determinant of the disease course.COPD is a collection of conditions, including emphysema,chronic bronchitis, mucus hypersecretion, bronchiolar and vascularremodeling, and sometimes the development of ﬁbrotic areasscattered throughout the parenchyma, that frequently coexist inhumans with this disease. Remarkable variation in the manifestationof COPD is observed among individuals with regard to the severityof symptoms and the rate of decline in FEV1 (14). Understandably,it is challenging to expect experimental rodent models to fullyrecapitulate the diverse aspects of the disease in humans.Future research should seek to identify the basis of COPDexacerbations and clarify the pathophysiological processes thatcontribute to the multiple phenotypes (susceptibility, severity, rate ofprogression, propensity to experience exacerbations, and emphysemaversus chronic bronchitis) caused by CS or by ﬂavored tobaccoproducts such as electronic nicotine delivery systems, cigars, andwaterpipes/hookahs. Different genetic loci may contribute to differentaspects of the disease, and may or may not be the same as thosethat determine susceptibility. Animal models constitute essential toolsbecause they can be used to study a deﬁned phenotype and to identifynovel candidate genes. In that regard, mouse strains that developCS-induced emphysema with or without goblet cell metaplasia, orthat develop emphysema with pulmonary ﬁbrosis or emphysemaassociated with pulmonary hypertension are currently available.The use of relevant mouse strains may thus help to identify candidategenes of probable biological relevance for the pathophysiology of adeﬁned phenotype, and to inform human studies seeking to identifygene linkage quantitative trait locus with COPD (9, 10). nAuthor disclosures are available with the text of this article atwww.atsjournals.org.Irfan Rahman, Ph.D.Department of Environmental MedicineUniversity of Rochester Medical CenterRochester, New YorkGiovanna De Cunto, Ph.D.Department of Molecular and Developmental MedicineUniversity of SienaSiena, ItalyIsaac K. Sundar, Ph.D.Department of Environmental MedicineUniversity of Rochester Medical CenterRochester, New YorkGiuseppe Lungarella, M.D.Department of Molecular and Developmental MedicineUniversity of SienaSiena, ItalyReferences1. Snider GL, Martorana PA, Lucey EC, Lungarella G. Animal models ofemphysema. In: Voelkel NF, MacNee W, editors. Chronic obstructivepulmonary disease. Hamilton, London: BC Decker Inc.;2002.pp. 237–256.2. Wright JL, Cosio M, Churg A. Animal models of chronic obstructivepulmonary disease. Am J Physiol Lung Cell Mol Physiol 2008;295:L1–L15.3. Martorana PA, Cavarra E, Lucattelli M, Lungarella G. Models for COPDinvolving cigarette smoke. Drug Discov Today Dis Models 2006;3:225–230.4. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D,Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-inducedemphysema in mice. Am J Pathol 2003;163:2329–2335.5. Bartalesi B, Cavarra E, Fineschi S, Lucattelli M, Lunghi B, Martorana PA,Lungarella G. Different lung responses to cigarette smoke intwo strains of mice sensitive to oxidants. Eur Respir J 2005;25:15–22.6. Cavarra E, Bartalesi B, Lucattelli M, Fineschi S, Lunghi B, Gambelli F,Ortiz LA, Martorana PA, Lungarella G. Effects of cigarette smokein mice with different levels of alpha(1)-proteinase inhibitorand sensitivity to oxidants. Am J Respir Crit Care Med 2001;164:886–890.7. Simet SM, Sisson JH, Pavlik JA, Devasure JM, Boyer C, Liu X, Kawasaki S,Sharp JG, Rennard SI, Wyatt TA. Long-term cigarette smoke exposurein a mouse model of ciliated epithelial cell function. Am J Respir Cell MolBiol 2010;43:635–640.8. Guerassimov A, Hoshino Y, Takubo Y, Turcotte A, Yamamoto M,Ghezzo H, Triantaﬁllopoulos A, Whittaker K, Hoidal JR, Cosio MG. Thedevelopment of emphysema in cigarette smoke-exposed mice isstrain dependent. Am J Respir Crit Care Med 2004;170:974–980.9. Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS,Ferris MT, Frelinger JA, Heise M, Frieman MB, et al. Genetic analysisof complex traits in the emerging Collaborative Cross. Genome Res2011;21:1213–1222.10. Radder JE, Gregory AD, Leme AS, Cho MH, Chu Y, Kelly NJ, Bakke P,Gulsvik A, Litonjua AA, Sparrow D, et al. Variable susceptibility tocigarette smoke–induced emphysema in 34 inbred strains of miceimplicates Abi3bp in emphysema susceptibility. Am J Respir Cell MolBiol 2017;57:367–375.11. Latini FR, Hemerly JP, Oler G, Riggins GJ, Cerutti JM. Re-expression ofABI3-binding protein suppresses thyroid tumor growth by promotingsenescence and inhibiting invasion. Endocr Relat Cancer 2008;15:787–799.12. Yao H, Yang SR, Edirisinghe I, Rajendrasozhan S, Caito S, Adenuga D,O’Reilly MA, Rahman I. Disruption of p21 attenuates lunginﬂammation induced by cigarette smoke, LPS, and fMLP in mice.Am J Respir Cell Mol Biol 2008;39:7–18.13. Tam A, Churg A, Wright JL, Zhou S, Kirby M, Coxson HO, Lam S, ManSF, Sin DD. Sex differences in airway remodeling in a mouse modelof chronic obstructive pulmonary disease. Am J Respir Crit CareMed 2016;193:825–834.14. Sandford AJ, Chagani T, Weir TD, Connett JE, Anthonisen NR,Pare´ PD. Susceptibility genes for rapid decline of lung functionin the lung health study. Am J Respir Crit Care Med 2001;163:469–473.EDITORIALSEditorials 271

Vulnerability and genetic susceptibility to cigarette smoke-induced emphysema in mice

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Vulnerability and genetic susceptibility to cigarette smoke-induced emphysema in mice

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